Hum. Reprod. Advance Access originally published online on October 24, 2006
Human Reproduction 2007 22(2):500-505; doi:10.1093/humrep/del416
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Effect of GnRH antagonists in FSH mildly stimulated intrauterine insemination cycles: a multicentre randomized trial
1 Università degli Studi di Milano and 2 Infertility Unit, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy
3 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology II, Università degli Studi di Milano, Via Commenda 12-20122, Milano, Italy. E-mail: piergiorgio.crosignani{at}unimi.it
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Abstract |
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BACKGROUND: The usefulness of GnRH antagonists in mild controlled ovarian hyperstimulation (COH) and intrauterine insemination (IUI) cycles is debated. METHODS: Two-hundred and ninety-nine couples with unexplained or mild male factor infertility were enrolled in this international multicentre randomized controlled trial. Women allocated to the GnRH antagonist group (n = 148) received 50 IU recombinant FSH starting on day 3 of the menstrual cycle and Ganirelix 0.25 mg daily starting from the day in which a follicle with a mean diameter of 13–14 mm was visualized at ultrasound. Women allocated to the control group (n = 151) were administered only 50 IU recombinant FSH starting on day 3 of the menstrual cycle. Couples were recruited only for their first treatment cycle. The primary outcome was the clinical pregnancy rate per initiated cycle. RESULTS: Baseline characteristics of the two treatment groups were similar. Clinical pregnancy rates per initiated cycle in women who did and did not receive GnRH antagonists were 12.2 and 12.6%, respectively (P = 1.00). The relative risk of conception (95% confidence interval) for the use of GnRH antagonists was 1.0 (0.5–1.9). CONCLUSIONS: In mild COH and IUI cycles, any benefit of the use of GnRH antagonists in improving pregnancy rates is <2-fold increase.
Key words: intrauterine insemination/mild ovarian hyperstimulation/GnRH antagonist
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Introduction |
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Unexplained subfertility is diagnosed in 20% of the couples after the initial diagnostic work-up. This number grows if we add couples with mild male infertility (Crosignani and Rubin, 2000
). This figure indicates that the clinical evaluation of infertility must be greatly improved and in particular that there is an urgent need of clinical tests looking at the quality of the oocyte and at the fertilizing ability of the semen (Guzick et al., 2001; ESHRE Capri Workshop Group, 2004). Because of these limitations, today there is a wide use of empirical treatments, in particular, intrauterine insemination (IUI). It is well known that IUI carried out during natural menstrual cycles is associated with low pregnancy rates (Guzick et al., 1999; Cohlen et al., 2001); this is why most of the clinics use IUI in controlled ovarian hyperstimulation (COH) cycles.
According to the largest available clinical studies, IUI in cycles stimulated with conventional doses of gonadotrophins induces a pregnancy in 10–15% of cases, with better results in couples with normal semen (Guzick et al., 1999; Gleicher et al., 2000; Dickey et al., 2005). Unfortunately, about 15–20% of the achieved pregnancies were twins and 5–10% triplets or more (Gleicher et al., 2000; Tur et al., 2001; Dickey et al., 2005). Because the reduction of iatrogenic multiple pregnancies is considered today the most important priority to prevent neonatal cerebral palsy (Kurinczuk, 2003), IUI in stimulated cycles has been marked as an unsafe technique (ESHRE Capri Workshop Group, 2000; Cohlen, 2005; Fauser et al., 2005) and an appropriate trial for the use of unifollicular or bifollicular stimulated IUI was called for (Edwards, 2003; Stewart, 2003). In line with this thinking, protocols of mild ovarian hyperstimulation are currently gaining consent (Goverde et al., 2000; Papageorgiou et al., 2004; Tur et al., 2005; Ragni et al., 2006). The effectiveness, safety profile and the best pharmacological and monitoring protocols of this approach remain however to be fully clarified.
A debated issue in this context is related to the usefulness of GnRH antagonists. This drug may be of benefit in this context because it has been demonstrated that it effectively prevents premature LH surge (Lambalk et al., 2006). This may theoretically allow better timing of insemination. The role of GnRH antagonist in COH–IUI cycles has been previously investigated in three randomized studies, but results were conflicting (Williams et al., 2004; Gomez-Palomares et al., 2005; Lambalk et al., 2006). To gain insights into this relevant aspect of infertility treatment, we set up an international multicentre trial aimed to evaluate the benefits of GnRH antagonists in a protocol of mild COH and IUI in terms of chance to conceive.
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Materials and methods |
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This randomized study was approved by the local Institutional review boards of the following 11 participating centres: Amsterdam, Athens, Barcelona, Budapest I (Forgacs Intezet), Budapest II (Infertility and IVF Center of Buda, St Jones Hospital), Cairo, Hradek Kralove, Lübeck, Milan, Palermo and Prague.
Patients who sought medical care for subfertility and who were selected for IUI were considered for study entry. Inclusion criteria were as follows: women aged 38 years, primary or secondary infertility lasting for at least 24 months, regular menstrual cycles, a body mass index (BMI) 
30 kg/m2, midluteal phase progesterone >6 ng/ml, day 3 serum FSH <10 IU/ml, normal uterine cavity and tubal patency assessed by hysterosalpingography and/or laparoscopy with chromosalpingography, normal semen analysis according to the World Health Organization criteria (WHO, 1999) or at least 5 million motile spermatozoa after semen preparation and normal morphology (5%) according to Kruger criteria and no previous IUI. Patients with monolateral tubal occlusion were included if the patent tube looked normal at laparoscopy. Patients with minimal or mild (stage I–II) endometriosis were also eligible. Conversely, women with endometriosis stage III–IV and/or pelvic inflammatory disease were excluded. Male factor subfertility was defined as basal semen analysis documenting semen concentration <20 million spermatozoa/ml and/or progressive motility <25% and/or sperm morphology <9% according to Kruger criteria (WHO, 1999). Couples were recruited only for their first treatment cycle. All patients gave their informed consent before entering the study.
Patients underwent a transvaginal ultrasonography on day 3 of the cycle and were subsequently randomized by means of a computer-generated list into two groups. An independent list was established for each study centre. Sealed opaque envelopes containing treatment allocation were opened after inclusion. Patients and physicians were not blinded to the treatment allocation. The therapeutic protocol of the study is illustrated in Figure 1. All subjects received 50 IU recombinant FSH (Puregon®, Organon, Oss, Netherlands) per day from the third day of the cycle. Ovarian stimulation was monitored by daily transvaginal ultrasound scans starting from the eighth day of the cycle (fifth day of ovarian stimulation). Patients allocated to the GnRH antagonist group were administered Ganirelix (Orgalutran®, Organon, Oss, Netherlands) at a dose of 0.25 mg/day starting from the day in which a follicle 
13–14 mm in mean diameter was visualized until hCG administration. Patients allocated to the control group were monitored in the same way but did not receive GnRH antagonist. In both groups, 5000 IU hCG was administered when a leading follicle with a mean diameter >18 mm was visualized. In the treatment group, if a leading follicle with a mean diameter >18 mm was detected at the first transvaginal ultrasound scan at the eighth day of the cycle, hCG was administrated the same day without prescribing GnRH antagonist. These cases were included in the treatment group. In both groups, insemination was performed 30–36 h after hCG injection. No luteal phase supplementation was prescribed. Cycles were cancelled if the total number of follicles with a mean diameter 14 mm was >2 and/or total number of follicles with a mean diameter 11 mm was >4 and/or serum estrogen was >800 pg/ml (hyper-response). Cancellation was also performed in the absence of follicular growth (poor response). In the control group, twice-daily urine tests for the occurrence of LH surge were recommended but not mandatory. Clinical pregnancy was defined as the ultrasound visualization of at least one intrauterine gestational sack, whereas ongoing pregnancy refers to pregnancies progressing beyond the first trimester. Ovarian hyperstimulation syndrome (OHSS) was diagnosed according to previously reported criteria (Aboulghar and Mansour, 2003).
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The sample size was calculated based on the assumptions that the expected clinical pregnancy rate in the control group was about 10% and stating as particularly relevant a 2-fold increase in the rate of success. Based on these assumptions and setting the type I and II errors to the usual levels of 0.05 and 0.20, respectively, the number of cases to be treated per arm was
200. A deadline of October 2005 for the recruitment of patients was also declared irrespective of the number of enrolled cases at that time. For this reason, the study was interrupted when the number of cases enrolled was lower than initially stated (150 cases per arm). Based on the above-mentioned assumptions, this sample size would have allowed us to detect at least a 2.2-fold increase in the rate of success. No interim analysis was initially decided.
Analyses were performed by the intention to treat: patients allocated to the GnRH antagonist group who did not receive the drug were included in the treatment group. Data were compared using 
2 test, Fisher exact test, Student’s t-test and non-parametric Wilcoxon test as appropriate (SPSS/Windows, Chicago, IL, USA). A binomial distribution model was used to calculate the 95% confidence interval (95% CI) of the pregnancy rate.
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Results |
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Between January 2004 and October 2005, 299 couples were recruited. The duration of the recruitment period in each participating centre lasted
1 year. The number of cases (controls + GnRH antagonist) according to study centre were as follows: Amsterdam = 26 (14 + 12), Athens = 21 (10 + 11), Barcelona = 23 (12 + 11), Budapest I = 28 (16 + 12), Budapest II = 32 (14 + 18), Cairo = 17 (9 + 8), Hradek Kralove = 21 (10 + 11), Lübeck = 5 (2 + 3), Milan = 70 (34 + 36), Palermo = 31 (15 + 16) and Prague = 25 (15 + 10). Baseline clinical characteristics of randomized patients are summarized in Table I. No significant differences according to study group were documented. Tubal patency was investigated through hysterosalpingography alone in 197 cases (65.9%), laparoscopy alone in 35 cases (11.7%) and both in 67 cases (22.4%). This figure was very similar in both arms of the study. Endometriosis stage I–II was laparoscopically documented in 13 (8.6%) and 8 (5.4%) cases in the control and treatment group, respectively (P = 0.37). The precise trial profile is illustrated in Figure 2. Overall, 38 couples did not complete the treatment cycle. Numbers (%) of dropouts in the control and GnRH antagonist groups were 20 (13.2%) and 18 (12.8%), respectively (P = 1.00). None of the patients discontinued because of an adverse event.
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Cycle characteristics according to treatment group are summarized in Table II. Duration of treatment was slightly longer in women receiving GnRH antagonist compared with controls (9.7 ± 2.3 and 9.1 ± 2.2 days, respectively, P = 0.02). Other variables did not significantly differ in the two study groups. In the treatment group, the mean ± SD and the median (inter quartile range) number of GnRH antagonist ampoules used were 3.4 ± 1.3 and 3 (3–4), respectively. Three patients (2.3%) were not prescribed the GnRH antagonist because of already meeting the criteria for hCG administration at the first transvaginal ultrasound scan on day 8. Two patients (1.5%) used two ampoules, whereas three (2.3%) had to use more than five ampoules; the vast majority of patients thus used three to five ampoules (122 cases corresponding to 93.9%).
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Pregnancy rate per started cycle and per completed cycle was extremely similar in the two groups (Table III). The pregnancy rates (95% CI) per initiated cycle in the control and GnRH antagonist groups were 12.6% (7.9–19.2%) and 12.2% (7.6–18.7%), respectively (P = 1.00). The corresponding odds ratio (95% CI) for pregnancy for the use of GnRH antagonist was 1.0 (0.5–1.9). Spontaneous abortion occurred in six women (16.2%), three cases per group. Thirty-four of the 37 pregnancies were singleton (91.9%). We observed three twin pregnancies (8.3%) and no high-order multiple pregnancies. They all occurred in the control group. One further extrauterine pregnancy was documented in the control group. When data were analysed by study centre, baseline characteristics were found to significantly differ among participating units but pregnancy rate did not (data not shown).
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Discussion |
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In this study, we failed to document any benefit of GnRH antagonist administration in mild COH and IUI in terms of chance to conceive. The clinical pregnancy rates per initiated cycle in women who did and did not receive GnRH antagonists were 12.2% and 12.6%, respectively. The corresponding odds ratio for pregnancy (95% CI) for the use of GnRH antagonist was 1.0 (0.5–1.9).
Some limitations of this study should be considered. Even though the study was randomized and the baseline characteristics of the two treatment groups were the same, it was not blinded. We believe that this limitation did not significantly influence the observed results because a relevant role of the placebo effect in this specific context is questionable. Another limitation that should be mentioned is that, due to economic constraints, the allocation system was not centralized. It cannot thus be completely excluded that there was no tampering at all with the allocation sequence. Finally, it should be underlined that the study was interrupted before enrolment of the entire calculated sample size. In this regard, it should be considered that the upper limit of the calculated 95% CI of the chances of success was 1.9, thus excluding benefits above a 2-fold increase in the rate of success with 95% confidence. This is below the level of relevance stated at the time of the calculation of the sample size. It is noteworthy that our results do not allow us to rule out some beneficial effect of GnRH antagonists. They simply support the conclusion that the benefit of these drugs, if present, is <2-fold increase in pregnancy rate.
Patients of both groups did not receive luteal phase supplementation in our study. This may represent a matter of concern. Previous studies indeed indicate that luteal phase deficiency is a common feature of cycles resulting from ovarian hyperstimulation and that pharmacological supplementation significantly improves pregnancy rate (Pritts and Atwood, 2002; Tarlatzis et al., 2006). Nevertheless, it is noteworthy that available evidence refers to ovarian hyperstimulation cycles performed using higher doses of gonadotrophins than those used in the present trial. Moreover, specific data on the benefits of luteal phase supplementation in patients receiving GnRH antagonist are scanty and questionable (Albano et al., 1997, 1999; De Jong et al., 2000; Ragni et al., 2001; Kolibianakis et al., 2003). Randomized trials aimed to assess whether this treatment improves pregnancy rate in this specific context are lacking. Overall, we did not believe that there is currently sufficient evidence to support the routine use of luteal phase supplementation in mild ovarian hyperstimulation cycles with or without GnRH antagonists. Further specific studies are required to draw firm conclusion on this issue.
Results from the present study are in line with those reported by Williams et al. (2004) and by Lambalk et al. (2006) but in contrast with those documented by Gomez-Palomares et al. (2005). In the first study, Williams et al. randomized 54 patients to receive 100 IU recombinant FSH for up to four cycles with or without Ganirelix. Pregnancy rates per initiated cycle in women who did (n = 52) and did not (n = 66) receive GnRH antagonists were 12 and 7%, respectively (not significant) (Williams et al., 2004). More recently, Lambalk et al. (2006) randomized 203 patients treated with mild COH to receive Ganirelix (n = 103) or placebo (n = 100) and observed pregnancy rates per started cycle of 13.6 and 13.0%, respectively (again, not significant). Conversely, Gomez-Palomares et al. documented a statistically significant benefit of GnRH antagonists in a randomized trial recruiting 82 patients who received 100 IU recombinant FSH/day. Pregnancy rates per initiated cycle in women who did (n = 40) and did not (n = 42) receive GnRH antagonists were 37.5 and 14.3%, respectively (P = 0.01) (Gomez-Palomares et al., 2005). Reasons to explain discrepancies among studies can herein only be hypothesized. Differences in baseline characteristics of recruited patients and/or in treatment protocols (such as for example the dose of recombinant FSH used) may have played a role. A publication bias cannot be excluded. Finally, the statistical power of these studies is generally low; in particular, it cannot be excluded that the statistically significant difference documented in the latest trial may have occurred by chance. Further large studies and future meta-analyses are required to definitely disentangle this issue.
If confirmed, the lack of a relevant effect of GnRH antagonists is surprising considering that the rate of premature LH surge has been reported to occur frequently in stimulated cycles. In women treated with mild COH, Lambalk et al. observed a LH rise in up to 28% of cycles. In this same study, these authors documented that in women treated with GnRH antagonist, this event occurred only in 3.9% of stimulated cycles. Moreover, none of the subjects with premature luteinization became pregnant (Lambalk et al., 2006). In this context, it is noteworthy that a similar result was also observed with GnRH agonist. The addition of this drug in COH–IUI cycles did not result in an increased pregnancy rate despite an effective reduction of premature luteinization (Dodson et al., 1991; Sengoku et al., 1994). These results are difficult to explain. Overall, it may be speculated that the benefits related to the prevention of the LH surge are balanced by the not well-understood detrimental effects of GnRH agonists or antagonists. In this regard, it is noteworthy that a modification of serum hormonal levels after initiation of GnRH antagonist has been reported (Lambalk et al., 2006).
Taking into account the warning raised against the use of IUI in stimulated cycles (Collins, 2003; Hughes, 2003; Kurinczuk, 2003; Stewart, 2003; Fauser et al., 2005), the overall pregnancy rate of 12–13% per starting cycle associated with a limited number of twins is the major success of the use of low-dose recombinant FSH for COH and IUI (Ragni et al., 2006). Even if comparisons among series should be done with caution due to extreme variability in baseline characteristics, it is noteworthy that the success rate observed in this trial is similar to the rate reported in COH–IUI cycles using higher doses of gonadotrophins, whereas the rate of multiple pregnancies is remarkably lower (Guzick et al., 1999; Gleicher et al., 2000; Tur et al., 2001; Dickey et al., 2005). Randomized study comparing high and low doses of gonadotrophins is however warranted before drawing reliable conclusions on this issue.
To further reduce the rate of multiple births, we employed strict cancellation criteria in this study. Cancellation criteria are currently widely used to limit the number of multiple pregnancies. Number of follicles, in particular number of follicles with a mean diameter between 11 and 15 mm, and serum levels of estrogens have been claimed to play a crucial role in determining the rate of multiple births. The optimal combination of criteria for cancellation has however not been defined and may depend on the protocol of stimulation used. Regardless of the cancellation criteria employed, protocols of higher doses of gonadotrophins may force physicians to interrupt an unacceptable high proportion of cases with a subsequent important economic and psychological burden. It is noteworthy that in both arms of our trial, the number of dropouts due to hyper-response is low (6.6 and 4.1% in the control and GnRH antagonists groups, respectively). A further interesting result of the present study is that a satisfactory pregnancy rate associated with a high rate of monofollicular cycles and a low twin rate was registered throughout all participating centres and obtained without a strict technical uniformity. This suggests a fairly good clinical practicability of this protocol.
In conclusion, this study does not support the routine use of GnRH antagonist in protocols of mild COH and IUI in terms of chances of success. Based on this evidence, should GnRH antagonists be definitively excluded from protocols of mild COH and IUI? We believe that some points need to be better defined before abandoning their use. First, the effects on the rate of multiple births remains to be elucidated. The use of GnRH antagonist may become of relevance if future studies will demonstrate that these drugs effectively reduce the rate of multiple births without impairing the chances of success. Unfortunately, the sample size recruited in this study is absolutely insufficient to disentangle this issue. When discussing the pros and cons of the use of GnRH antagonists in IUI cycles, some practical aspects have also to be underlined. The possibility to prevent weekend insemination has been recently emphasized (Checa et al., 2006). Strict cycle monitoring such as serial transvaginal sonography and/or frequent urine tests is not essential when using GnRH antagonists because the occurrence of a premature LH surge is quite rare. The longer duration of stimulation in the GnRH antagonist group observed in this study may be consequent to the confidence of physicians in this regard. This aspect should be considered in future cost-effectiveness analyses on this topic.
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Footnotes |
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* M.A.Aboulghar, The Egyptian IVF-ET Center, Cairo, Egypt; A.Allegra, Reproductive Medicine Unit, ANDROS Day Surgery, Palermo, Italy; R.Buxaderas, Reproductive Medicine Service, Institut Universitari Dexeus, Barcelona, Spain; V.Forgacs, Forgacs Institute of Assisted Reproduction, Budapest, Hungary; G.Griesinger, Department of Obstetrics-Gynaecology, University Clinic of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany; R.Homburg, Division of Reproductive Medicine, Vrije Universiteit Medical Center, Amsterdam, The Netherlands; M.Hrehorcak, Center of Reproductive Medicine and Reproductive Genetics, 2nd Medical Faculty, Charles University, Prague, Czech Republic; J.Konc, Infertility and IVF Center of Buda, St. John’s Hospital, Budapest, Hungary; L.Mamas, Neogenesis, IVF Center, Athens, Greece; G.Ragni, Infertility Unit, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy; V.Silhan, Center of Assisted Reproduction SANUS, Hradec Kralove, Czech Republic.
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Submitted on July 11, 2006; resubmitted on September 6, 2006; accepted on September 25, 2006.
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  N. N. Mahajan, K. N. Mahajan, and R. N. Soni Effect of GnRH antagonists in FSH mildly stimulated intrauterine insemination cycles: a multicentre randomized trial Hum. Reprod., October 1, 2007; 22(10): 2795 - 2795. [Full Text] [PDF]
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P. G. Crosignani and E. Somigliana Reply: Effect of GnRH antagonists in FSH mildly stimulated intrauterine insemination cycles: a multicentre randomized trial Hum. Reprod., October 1, 2007; 22(10): 2796 - 2796. [Full Text] [PDF]
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